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Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell receptor signaling by recruitment of inhibitory molecules.

To maintain various T cell responses and immune equilibrium, activation signals triggered by T cell antigen receptor (TCR) must be regulated by inhibitory signals. Gab2, an adaptor protein of the insulin receptor substrate-1 family, has been shown to be involved in the downstream signaling from cytokine receptors. We investigated the functional role of Gab2 in TCR-mediated signal transduction. Gab2 was phosphorylated by ZAP-70 and co-precipitated with phosphoproteins, such as ZAP-70, LAT, and CD3zeta, upon TCR stimulation. Overexpression of Gab2 in Jurkat cells or antigen-specific T cell hybridomas resulted in the inhibition of NF-AT activation, interleukin-2 production, and tyrosine phosphorylation. The structure-function relationship of Gab2 was analyzed by mutants of Gab2. The Gab2 mutants lacking SHP-2-binding sites mostly abrogated the inhibitory activity of Gab2, but its inhibitory function was restored by fusing to active SHP-2 as a chimeric protein. A mutant with defective phosphatidylinositol 3-kinase binding capacity also impaired the inhibitory activity, and the pleckstrin homology domain-deletion mutant revealed a crucial function of the pleckstrin homology domain for localization to the plasma membrane. These results suggest that Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transduction by mediating the recruitment of inhibitory molecules to the TCR signaling complex.

Pubmed ID: 11572860

Authors

  • Yamasaki S
  • Nishida K
  • Hibi M
  • Sakuma M
  • Shiina R
  • Takeuchi A
  • Ohnishi H
  • Hirano T
  • Saito T

Journal

The Journal of biological chemistry

Publication Data

November 30, 2001

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antigens, CD
  • Antigens, CD3
  • Antigens, Differentiation, T-Lymphocyte
  • Binding Sites
  • Blotting, Western
  • Carrier Proteins
  • Cell Line
  • Cytokines
  • DNA
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • Hybridomas
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Lectins, C-Type
  • Luciferases
  • Lymphocyte Activation
  • Membrane Proteins
  • Mice
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • Phosphoproteins
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Protein-Tyrosine Kinases
  • Receptors, Antigen, T-Cell
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Signal Transduction
  • Structure-Activity Relationship
  • Transfection
  • Tyrosine
  • ZAP-70 Protein-Tyrosine Kinase
  • src Homology Domains